Thermodynamic basis of protein-ligand interactions

Question 1

What are the most common target for drug discovery?

Answer 1

G-protein coupled receptors

Protein Kinases are another important class

Question 2

What targets are viewed as ‘undruggable’ ?

Answer 2

protein-protein interactions

Question 3

What must a drug fit into?

Answer 3

The binding site

Question 4

What often bears a resemblance to the substrate?

Answer 4

enzyme inhibitors

Question 5

what does the first substrate induce?

Answer 5

Induces fit of second substrate in enzyme

Question 6

what happens after both substrates are bound?

Answer 6

products are released, enzyme reverts to unbound conformation

Question 7

what percentage of protein binding site will have significant flexibility?

Answer 7

30%

Question 8

what are proteins involved in?

Answer 8

signal transduction

–> such as G-protein coupled receptors or kinases. They must be able to adopt multiple conformations as part of the switching mechanism

Question 9

What does binding of a ligand to a protein lead to?

Answer 9

Leads to a change in the protein shape thus causing a change in the binding of the next protein in the signalling cascade

Question 10

What is Kd and what is it equal to?

Answer 10

Dissociation constant
Kd = [P][L]/ = moldm-3
         [PL]
Therefore, when [L] = Kd
, [P] = [PL] 

P = Protein 
L = ligand

Question 11

What is true when L = Kd?

Answer 11

half of the ligand binding sites are occupied. (the amount of free protein [P] and the amount of ligand-bound protein [PL] are equal)

Question 12

What is the relationship between the strength of the binding and the concentration required to achieve 50% occupancy?

Answer 12

The stronger the binding site, the lower the concentration required to achieve 50% occupancy

Question 13

What happens to water molecules when a protein binds to a ligand?

Answer 13

Water molecules that were previously bound to the protein and/or ligand dissociate and are returned to bulk state (some waters may be bound too tightly to be displaced)

Question 14

When do ligands bind to proteins?

Answer 14

when it is energetically favoured.

Gibbs free energy is a negative value

Question 15

What do hydrophilic compounds bind predominantly through?

Answer 15

Bonding interactions:
High requirement for these interactions to be optimal for the target (as need to
pay the energetic price of breaking interactions with water)

Question 16

What do lipophilic compounds bind predominantly through?

Answer 16

Entropic effects:
Effectively pushed out by water into an environment that is less unfavoured.
Interaction with protein my be much less specific (though compound still needs to
fit in the binding site)